Endothelial cells in the innate response to allergens and initiation of atopic asthma

Abstract

Protease-activated receptor 2 (PAR-2), an airway epithelial pattern recognition receptor (PRR), participates in the genesis of house dust mite-induced (HDM-induced) asthma. Here, we hypothesized that lung endothelial cells and proangiogenic hematopoietic progenitor cells (PACs) that express high levels of PAR-2 contribute to the initiation of atopic asthma. HDM extract (HDME) protease allergens were found deep in the airway mucosa and breaching the endothelial barrier. Lung endothelial cells and PACs released the Th2-promoting cytokines IL-1α and GM-CSF in response to HDME, and the endothelium had PAC-derived VEGF-C-dependent blood vessel sprouting. Blockade of the angiogenic response by inhibition of VEGF-C signaling lessened the development of inflammation and airway remodeling in the HDM model. Reconstitution of the bone marrow in WT mice with PAR-2-deficient bone marrow also reduced airway inflammation and remodeling. Adoptive transfer of PACs that had been exposed to HDME induced angiogenesis and Th2 inflammation with remodeling similar to that induced by allergen challenge. Our findings identify that lung endothelium and PACs in the airway sense allergen and elicit an angiogenic response that is central to the innate nonimmune origins of Th2 inflammation.

An endothelial microRNA-1–regulated network controls eosinophil trafficking in asthma and chronic rhinosinusitis

“…Third, miR-1 targets had inverse correlations with miR-1 and direct correlations with eosinophilia in clinical samples. These findings are consistent with the role of endothelium as an ''orchestrator'' of the inflammatory response [52][53][54][55] and suggest that miR-1 plays critical roles in the initiation (through release of alarmins, such as TSLP) and sustenance (through SELP, MPL, and CCL26) of the eosinophilic response.…”

Endothelial Cells in Asthma

“…More recent studies have utilized the HDME model, which is clinically relevant as house dust mite allergens are a potent inducer of asthma worldwide [96]. HDMEexposed mice present with increased accumulation of PACs, increased vascularity of the airway, airway inflammation, and airway hyperresponsiveness [77,97]. VEGFR-3 and its ligand VEGF-C are critical in new vessel sprouting in asthmatic angiogenesis [97].…”

“…HDMEexposed mice present with increased accumulation of PACs, increased vascularity of the airway, airway inflammation, and airway hyperresponsiveness [77,97]. VEGFR-3 and its ligand VEGF-C are critical in new vessel sprouting in asthmatic angiogenesis [97]. VEGFR-3 is expressed exclusively in blood vessels actively undergoing angiogenesis, and this VEGFR-3 expression is known to increase when cells are exposed to HDME [97].…”

“…VEGFR-3 and its ligand VEGF-C are critical in new vessel sprouting in asthmatic angiogenesis [97]. VEGFR-3 is expressed exclusively in blood vessels actively undergoing angiogenesis, and this VEGFR-3 expression is known to increase when cells are exposed to HDME [97]. HDME exposure promotes differentiation and proliferation of PACs, induces secretion of VEGF-C, and upregulates protease-activated receptor 2 (PAR-2) [97][98][99][100][101][102].…”

“…VEGFR-3 is expressed exclusively in blood vessels actively undergoing angiogenesis, and this VEGFR-3 expression is known to increase when cells are exposed to HDME [97]. HDME exposure promotes differentiation and proliferation of PACs, induces secretion of VEGF-C, and upregulates protease-activated receptor 2 (PAR-2) [97][98][99][100][101][102]. PAR-2 is a key house dust mite allergen-sensing receptor mainly expressed on airway epithelial cells, endothelial cells, and dendritic cells [103][104][105][106][107][108][109].…”